KR20070088507A - Crystalline forms of carvedilol and processes for their preparation - Google Patents

Abstract

This invention relates to a novel crystalline form of carvedilol, to processes for its preparation, to compositions containing it and to its use in medicine. This invention further relates to a novel process for preparing crystalline carvedilol Form II.

Description

Crystalline form of carvedilol and a method for preparing the same {CRYSTALLINE FORMS OF CARVEDILOL AND PROCESSES FOR THEIR PREPARATION}

Related Applications

This application claims the benefit of US Provisional Application No. 60 / 689,776, filed June 9, 2005, which is incorporated herein by reference.

Field of invention

The present invention relates to the crystalline form of carvedilol.

Carvedylol, (±) -1- (carbazol-4-yloxy) -3-[[(2- (o-methoxyphenoxy) ethyl] amino] -2-propanol has α ₁ -blocking activity Non-selective β-adrenergic blocker Carvediol is a racemic mixture having the formula:

Cabeddiol

Carvedilol is an active ingredient of COREG®, which is indicated to be used in the treatment of congestive heart failure and in the control of hypertension. Carvedilol is a multi-acting drug whose beta-blocking activity affects the response to specific nerve shocks in the body part. Usually, beta-blockers reduce the heart demand for blood and oxygen by reducing the workload of the heart. In addition, carvedilol is known to be a vasodilator that results primarily from the alpha-adrenoceptor blockade. Multiple action of carvediol corresponds to the antihypertensive efficacy of the drug and to the effectiveness of the drug in controlling congestive heart failure.

International Patent Application No. WO 99/05105 discloses carvedilol polymorphic forms designed in Form I and Form II.

International Patent Application No. WO 02/00216 discloses carvedilol polymorphic forms designed in Form III and Form IV. Also disclosed are Form V or solvates thereof with methyl ethyl ketone.

International Patent Application No. WO 03/059807 discloses a carvedilol polymorphic form designed with Form VI or a solvate thereof, and a process for the preparation of the polymorphic form with ethyl acetate, including a seeding step.

The present invention relates to the physical properties of the solid state of carvedilol.

These properties can be influenced by controlling the conditions under which carvedilol is obtained in solid form. Physical properties of the solid state include, for example, the flowability of the milled solid. The fluidity affects the ease with which the material is handled during processing into the chemical. When particles of powdered compounds do not flow quickly with respect to each other, formulation specialists should take this into account in the development of tablet or capsule formulations, which may include glidants such as colloidal silicon dioxide, talc, starch or 3 It may be necessary to use basic calcium phosphate.

Another important solid state property of pharmaceutical compounds is the rate of dissolution in the aqueous fluid. The rate of dissolution of the active ingredient in the patient's gastric juice may have a therapeutic result because the rate of dissolution provides an upper limit to the rate at which the orally administered active ingredient can reach the bloodstream of the patient. Dissolution rates are also a consideration when formulating syrups, elixirs and other liquid agents. The solid state form of the compound may also affect the behavior of the compound upon compression and the storage stability of the compound.

These practical physical properties can be influenced by the placement and orientation of molecules in the unit cell, which defines the specific polymorphic form of the material. Polymorphic forms can cause different thermal behaviors than those of amorphous materials or another polymorphic form. This thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and can be used to distinguish some polymorphic forms from others. In addition, specific polymorphic forms can produce clear spectroscopic properties that can be detected by powder X-ray crystallography, solid state ¹³ C NMR spectroscopy or infrared spectrometers.

The present invention also relates to solvates of carvedylol. When the material crystallizes out of solution, the material can capture particles of the solvent at regular intervals in the crystal lattice. In addition, solvation affects the practical physical properties of the solid state such as flowability and dissolution rate.

 One of the most important physical properties of pharmaceutical compounds capable of forming polymorphs or solvates is the solubility of the compounds in aqueous solutions, in particular the solubility of the compounds in patient gastric juices. Another important property relates to the ease of processing the form into a pharmaceutical formulation, since the tendency of the powdered or granulated form to flow and the surface properties determine whether the crystals of the form adhere to each other when pressing the tablets into tablets. .

The discovery of novel polymorphic forms and solvates of pharmaceutically useful compounds offers new opportunities to improve the performance properties of pharmaceutical products. This expands the list of substances that formulation scientists can use, for example, to design pharmaceutical dosage forms of drugs with targeted release profiles or other desired properties.

Summary of the Invention

The present invention provides an X-ray powder diffraction pattern with peaks at about 4.3, 10.6, 11.1, 15.6 and 21.2 ± 0.2 ° 2θ; And a DSC thermogram with an endothermic peak at about 60 ° C. and 113 ° C. to provide a crystalline form of carvedilol.

Brief description of the drawings

Figure 1 illustrates the PXRD pattern for the carvedilol form of the present invention.

Figure 2 illustrates a DSC thermal analysis of the carvedilol form of the present invention.

3 illustrates a TGA thermal analysis of the carvedilol form of the present invention.

4 illustrates the PXRD pattern of Carvedilol Form II.

Detailed description of the invention

In one embodiment, the invention provides an X-ray powder diffraction pattern having peaks at about 4.3, 10.6, 11.1, 15.6 and 21.2 ± 0.2 ° 2θ; And a DSC thermogram with endothermic peaks at about 60 ° C. and 113 ° C. to provide a crystalline form of carvedilol.

The crystalline form can be further characterized by an X-ray powder diffraction pattern with peaks at about 8.5, 10.1, 12.7, 13.6, 16.6, 17.0, 19.1, 19.9, 20.3, 25.0, 25.4 ± 0.2 ° 2θ.

The crystalline forms of the present invention may be further characterized by TGA, which exhibits a weight loss of about 40% in the temperature range of 25-60 ° C.

The crystalline form of the present invention may be ethyl acetate solvate.

As used herein, the term "clean flask" means a flask that has been washed with an organic solvent. Preferably, the flask should not be washed with ethyl acetate to leave traces of carvedilol seed, which allows for spontaneous crystallization of the crystalline form of the present invention upon entering the supersaturation zone.

In another aspect, the present invention provides a method for preparing the crystalline form, the method comprising providing a solution of carvedilol in ethyl acetate in a clean flask, cooling the solution to a temperature below about 10 ° C. to precipitate Obtaining and recovering the crystalline form.

The solution is preferably provided at a temperature of about 70 ° C to about 78 ° C, preferably at a temperature of about 70 ° C to about 75 ° C.

It is preferable that the solution is stirred.

The solution is preferably cooled to a temperature of about 0 to about 5 ° C.

In another aspect, the present invention provides a method of preparing crystalline carvedilol characterized by an X-ray powder diffraction pattern (Form II) having peaks at about 5.9, 14.9, 17.6, 18.5 and 24.4 ± 0.2 ° 2θ. The method comprises drying the crystalline carvedilol characterized by an X-ray powder diffraction pattern with peaks at about 4.3, 10.6, 11.1, 15.6 and 21.2 ± 0.2 ° 2θ.

The drying step is preferably performed at a temperature of about 30 ° C to about 100 ° C, more preferably at a temperature of about 40 ° C to about 60 ° C, most preferably at a temperature of about 50 ° C.

For those skilled in the art, the required time to obtain carvedilol form II depends, among other factors, on the amount of wetted carvedilol form of the present invention to be dried, and the drying temperature, taking periodic XRD You can decide.

The crystalline form of the present invention exhibits a higher degree of crystallinity compared to Forms V and VI. This crystallinity is evidenced by the sharper XRD peaks and is an important factor that can affect the solubility of the crystal form.

The pharmaceutical composition of the present invention contains the carvedylol form described above, optionally in admixture with other crystalline forms and / or other active ingredients such as hydrochlorothiazide. In addition to the active ingredient (s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for various uses.

Diluents increase the bulk of the solid pharmaceutical composition and can make formulations containing the composition easier for the patient or caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (eg, Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, deck Straight, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g. Eudragit®), potassium chloride, powder Cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compressed into formulations, such as tablets, may include excipients having a function that includes helping to bind the active ingredient and other excipients that include together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomers (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. For example, Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g. , Kollidon®, Plasdone®), pregelatinized starch, sodium alginate or starch.

The dissolution rate of the solid pharmaceutical composition compressed in the stomach of the patient can be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol @ Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdon®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polyacrylic potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycol Rates (eg, Explotab®) or starch, including but not limited to.

Glidants can be added to improve the flow characteristics of the uncompressed solid composition and to improve the accuracy of administration. Excipients that can act as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and / or tribasic calcium phosphate.

When a formulation, such as a tablet, is prepared by compression of a powdered composition, the composition is pressure treated from a punch and a die. Some excipients and active ingredients have a tendency to adhere to the surfaces of punches and dies, which can lead to products with pitting and other surface irregularities. Glidants can be added to the composition to reduce adhesion of the product to the die and to facilitate peeling of the product from the die. Glidants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium Stearyl fumarate, stearic acid, talc, and / or zinc stearate.

Flavors and flavor enhancers make the formulations better fit the patient's mouth. Flavors and flavor enhancers common to the medicaments that may be included in the compositions of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol or tartaric acid

Solid and liquid compositions may also be stained with any pharmaceutically acceptable colorant to improve the appearance of the product and unit dosage levels and / or to facilitate patient identification at the product and dosage unit levels.

In the liquid pharmaceutical composition of the present invention, carvedilol and any other solid excipients described above are dissolved or suspended in a carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifiers to uniformly disperse the active ingredient or other excipient that is not soluble in the liquid carrier throughout the composition. Emulsifiers that may be useful in the liquid compositions of the invention include, for example, gelatin, egg yolks, casein, cholesterol, acacia, tragaganth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol or Cetyl alcohol, including but not limited to.

The liquid pharmaceutical composition of the present invention may also contain a viscosity-enhancing agent to improve the appetite of the product and / or to coat the inner surface of the gastrointestinal tract. Such agents include acacia, alginate bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose , Maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacanth or xanthan gum.

Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and / or invert sugar can be added to improve taste.

Preservatives and chelating agents such as alcohols, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels for digestion to improve storage stability.

In addition, the liquid compositions according to the invention may contain buffers such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

The choice of excipients and amounts to be used can be readily determined by the formulation technician based on the experience and considerations of standard procedures and reference work in the art.

Solid compositions of the present invention include powders, granules, aggregates and compressed compositions.

The carvedilol forms described above may be administered to treat congestive heart failure and hypertension (by means of delivering the active ingredient) to parts of the body where beta-blocking activity exerts a therapeutic effect on the patient. For example, administration can be oral, buccal, parenteral (including subcutaneous, intramuscular and intravenous), rectal, inhaler or ocular administration. Although the most suitable route in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral administration. Carvedilol Form VI or Carvedilol Crystalline Form of the present invention can be easily administered in oral unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. The formulations include tablets, powders, capsules, sachets, troches or lozenges as well as formulations such as liquid syrups, suspensions or elixirs.

The active ingredient (s) and excipients can be formulated into compositions and formulations according to methods known in the art.

Compositions for tableting or capsule filling can be prepared by wet granulation. In the wet granulation method, some or all of the active ingredient and excipients in powder form are mixed and then further mixed in the presence of a liquid, typically water, which causes the powder to agglomerate to form granules. This granule is screened and / or milled, dried and then screened and / or milled to a desired particle size. The granulate can then be tableted or tableted after the addition of excipients such as glidants and / or glidants.

The composition for tableting can be easily prepared by dry mixing. In practice, for example, a mixed composition of the active ingredient and excipients can be compressed into slugs or sheets and then ground into compressed granules. The compressed granules can then be compressed into tablets.

As an alternative to dry granulation, the mixed composition can be compressed directly into a compressed formulation using direct compression techniques. Direct compression procedures can produce more uniform tablets without granules. Excipients well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and / or colloidal silica. Appropriate use of these excipients and other excipients in direct compression tableting is well known to those skilled in the art with experience and skills in the specific formulation difficulties of direct compression tableting.

The capsule filling of the present invention may comprise any of the abovementioned mixtures and granules described with regard to tableting, provided that such mixtures and granules are not subjected to the final tableting step.

More specifically, tablets may be formulated, for example, by mixing the composition and compressing the mixture directly in a tableting machine.

Capsules can be prepared, for example, by filling a gelatin capsule half with the tablet composition and capping the capsule with another half of the gelatin capsule.

Simple parenteral compositions for injection are prepared, for example, by combining the carvedilol form VI and carvedilol crystalline forms of the invention, sterile polypropylene glycol and sterile water, and sealing the composition under sterile conditions in sterile vials. can do.

Capsules, tablets and lozenges and other unit dosage forms preferably contain formulation levels of about 1 mg to about 100 mg of the carvedilol form described above.

The following examples are given for the purpose of illustrating the invention and should not be construed as limiting the scope or spirit of the invention.

device

XRD

XRD diffraction was performed on an X-ray powder diffractometer, Scintag model X'TRA, Cut-tube, solid state detector. Scanning parameters range from 2-40 deg. 2θ, continuous scan rate: 3.00 3.00 deg./min.

Thermal analysis

DSC thermal analysis was performed on DSC821e, on Mettler Toledo, sample weight: 3 mg, and heating rate: 10 ° C / min.

TGA thermal analysis was performed on a METTLER TG50 at sample weight: 18 mg and heating rate: 10 ° C./min.

Example  1-of the present invention Carvedilol  Form of Manufacturing Method

50 g of carvedilol and 500 ml of ethyl acetate were poured into a clean flask and the slurry was heated to a temperature higher than 70 ° C. to obtain sufficient dissolution. This solution was cooled to about 0-5 ° C. At a temperature of about 5-10 ° C., spontaneous precipitation occurred. The solid material was filtered off and washed with ethyl acetate. The obtained wet material was the crystalline form of the present invention.

Example  2-Crystal Form of the Invention as Form II Converting  Way

Carvedylol crystal forms of the present invention were prepared according to Example 1. The wet material was dried at about 50 ° C. XRD represents Form II content for dry matter.

Claims (5)

X-ray powder diffraction pattern with peaks at about 4.3, 10.6, 11.1, 15.6, and 21.2 ± 0.2 ° 2θ; And DSC thermal analysis with endothermic peaks at about 60 ° C and 113 ° C Crystalline form of carvedilol characterized by data selected from. The crystalline form of carvedilol of claim 1 characterized by an X-ray powder diffraction pattern with peaks at about 4.3, 10.6, 11.1, 15.6 and 21.2 ± 0.2 ° 2θ. The method of claim 1 or 2, further characterized by an X-ray powder diffraction pattern with peaks at about 8.5, 10.1, 12.7, 13.6, 16.6, 17.0, 19.1, 19.9, 20.3, 25.0, 25.4 ± 0.2 ° 2θ. Crystalline form of carvedilol. 4. The crystalline form of carvedilol according to claim 2 or 3, further characterized by DSC thermal analysis with endothermic peaks at about 60 ° C and 113 ° C. 5. The crystalline form of carvedilol according to claim 2, further characterized by TGA exhibiting a weight loss of about 40% in the temperature range of 25-60 ° C. 6.

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